Mitochondrial myopathy with exercise intolerance and retinal dystrophy in a sporadic patient with a G583A mutation in the mt tRNAphe gene

Darín, Niklas; Kollberg, Gittan; Ar, Moslemi; Tulinius, M.; Holme, Elisabeth; Grönlund, Marita Andersson; Andersson, Susann; Oldfors, Anders

doi:10.1016/j.nmd.2006.05.010

Cited by 18 publications

(13 citation statements)

References 9 publications

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“…Such sporadic mutations have been reported in other patients with the same mitochondrial transfer RNA phenylalanine gene mutation. 12,16 • This report describes the case of a girl with mitochondrial sensorineural hearing loss • Cochlear implantation was effective, and improved the patient's quality of life • The mitochondrial DNA 625G>A mutation may be pathogenic for syndromic hearing loss Accordingly, we conclude that the m.625G>A transition may cause mitochondrial respiratory dysfunction and syndromic hearing loss. Another standard muscle biopsy and cybrid study would clarify the pathogenicity of the m.625G>A transition.…”

Section: Discussionmentioning

confidence: 88%

Successful cochlear implantation in a patient with mitochondrial hearing loss and m.625G>A transition

et al. 2011

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Objective: We present a patient with mitochondrial hearing loss and a novel mitochondrial DNA transition, who underwent successful cochlear implantation.Case report: An 11-year-old girl showed epilepsy and progressive hearing loss. Despite the use of hearing aids, she gradually lost her remaining hearing ability. Laboratory data revealed elevated lactate levels, indicating mitochondrial dysfunction. Magnetic resonance imaging showed diffuse, mild brain atrophy. Cochlear implantation was performed, and the patient's hearing ability was markedly improved. Whole mitochondrial DNA genome analysis revealed a novel heteroplasmic mitochondrial 625G>A transition in the transfer RNA gene for phenylalanine. This transition was not detected in blood DNA from the patient's mother and healthy controls. Mitochondrial respiratory chain activities in muscle were predominantly decreased in complex III.Conclusion: This case indicates that cochlear implantation can be a valuable therapeutic option for patients with mitochondrial syndromic hearing loss.

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Section: Discussionmentioning

confidence: 88%

Successful cochlear implantation in a patient with mitochondrial hearing loss and m.625G>A transition

et al. 2011

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“…1) (2)(3)(4)(38)(39)(40)(41)(42). To investigate the pathogenic mechanisms of these mutations, we used the corresponding WT and mutant forms of in vitro-transcribed hmttRNA Phe in aminoacylation experiments.…”

Section: Hmt-trna Phe Pathogenic Mutations Cause Aminoacylation Defectsmentioning

confidence: 99%

“…1) (2)(3)(4)(38)(39)(40)(41)(42), including a G34A anticodon variant associated with MERRF syndrome. Anticodon pathogenic mutations are rare in hmt-tRNAs, the only other known example being the G36A mutation of hmt-tRNA Pro (G15990A) for which the pathogenic mechanism remains obscure (43).…”

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confidence: 99%

Pathogenic mechanism of a human mitochondrial tRNA ^Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

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Roy

Qin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Human mitochondrial tRNA (hmt-tRNA) mutations are associated with a variety of diseases including mitochondrial myopathies, diabetes, encephalopathies, and deafness. Because the current understanding of the precise molecular mechanisms of these mutations is limited, there is no efficient method to treat their associated mitochondrial diseases. Here, we use a variety of known mutations in hmt-tRNA Phe to investigate the mechanisms that lead to malfunctions. We tested the impact of hmt-tRNA Phe mutations on aminoacylation, structure, and translation elongation-factor binding. The majority of the mutants were pleiotropic, exhibiting defects in aminoacylation, global structure, and elongation-factor binding. One notable exception was the G34A anticodon mutation of hmt-tRNA Phe (mitochondrial DNA mutation G611A), which is associated with MERRF (myoclonic epilepsy with ragged red fibers). In vitro, the G34A mutation decreases aminoacylation activity by 100-fold, but does not affect global folding or recognition by elongation factor. Furthermore, G34A hmt-tRNA Phe does not undergo adenosine-to-inosine (A-to-I) editing, ruling out miscoding as a possible mechanism for mitochondrial malfunction. To improve the aminoacylation state of the mutant tRNA, we modified the tRNA binding domain of the nucleus-encoded human mitochondrial phenylalanyl-tRNA synthetase, which aminoacylates hmt-tRNA Phe with cognate phenylalanine. This variant enzyme displayed significantly improved aminoacylation efficiency for the G34A mutant, suggesting a general strategy to treat certain classes of mitochondrial diseases by modification of the corresponding nuclear gene.aminoacyl-tRNA synthetase ͉ translation ͉ mitochondria

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“…Mitochondrial deficiencies accumulating with time are crucial to many pathophysiological processes such as Parkinson's disease, Alzheimer's disease, diabetes mellitus, liver disease, muscle dystrophy, cardiomyopathy, and cancer. 3,7,10 As an important subcellular compartment in almost all kinds of eukaryotic cells, mitochondria have the structure that contains the outer membrane, the intermembrane space, the inner membrane, and the matrix. The inner membrane is highly folded into cristae, in which there are the complexes of electron transport chain and ATP synthase that control the basic rates of cellular metabolism.…”

Section: Introductionmentioning

confidence: 99%

Membrane Deformability and Membrane Tension of Single Isolated Mitochondria

et al. 2008

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Abstract-Mitochondria dynamics is crucial to many biological processes such as mitochondria fusion and fission, which is highly correlated to the mechanics of single mitochondria. However, the mechanobiological coupling of mitochondria has been poorly understood. Here membrane deformability and membrane tension of individual mitochondria isolated from MtDsRed labeled human embryonic T-Rex-293 kidney cells were measured using a micropipette aspiration assay. The results demonstrated that membrane deformation of isolated mitochondria exhibited an elastic transition phase followed by an equilibrium phase, and mitochondrial membrane tension was proportional to the area compressibility. It was also indicated that mitochondrial membrane deformability was significantly affected by physical-chemical factors such as osmotic pressure or pH value, and was further correlated to mitochondrial functionality in different respiratory states and Ca 2+ regulation. These findings provide a new insight into understanding the mechanical regulation of mitochondrial physiology.

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Mitochondrial myopathy with exercise intolerance and retinal dystrophy in a sporadic patient with a G583A mutation in the mt tRNAphe gene

Cited by 18 publications

References 9 publications

Successful cochlear implantation in a patient with mitochondrial hearing loss and m.625G>A transition

Successful cochlear implantation in a patient with mitochondrial hearing loss and m.625G>A transition

Pathogenic mechanism of a human mitochondrial tRNA ^Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Membrane Deformability and Membrane Tension of Single Isolated Mitochondria

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Mitochondrial myopathy with exercise intolerance and retinal dystrophy in a sporadic patient with a G583A mutation in the mt tRNAphe gene

Cited by 18 publications

References 9 publications

Successful cochlear implantation in a patient with mitochondrial hearing loss and m.625G>A transition

Successful cochlear implantation in a patient with mitochondrial hearing loss and m.625G>A transition

Pathogenic mechanism of a human mitochondrial tRNA Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Membrane Deformability and Membrane Tension of Single Isolated Mitochondria

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Pathogenic mechanism of a human mitochondrial tRNA ^Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome